The aim of the proposed study is to evaluate the efficacy of a novel chemopreventive strategy based on the delivery of microRNA mimetics in experimental models of lung carcinogenesis in mice. MicroRNAs are noncoding small RNAs acting as post-transcriptional repressors and regulators of gene expression. MicroRNAs are grossly dysregulated in human cancers, including lung cancer. The microRNAs that are under-expressed in cancer can be functionally classified as tumor-suppressors while those that are over-expressed act as oncogenes. The let-7 microRNA family is a well characterized family of tumor suppressors whose genes map to different chromosomal regions that are frequently deleted in lung cancer. Let-7 microRNAs negatively regulate multiple oncogenes including RAS, MYC, and HMGA2, as well as cell-cycle progression regulator genes such as CDC25A, CDK6, and cyclin D2. Recent results have reported on the development of an aerosolized let-7B mimetic that inhibited benzo[a]pyrene-induced lung adenoma volume by 72% in A/J mice (Nano Lett., 19: 2231-2242, 2019), although mice in this model rarely develop adenocarcinomas. As lung adenocarcinomas and squamous cell carcinomas account for ~80% of all human cancer histological subtypes, the objectives of this Task Order are to determine 1) if aerosolized let-7b will be effective against the two most common lung tumor subtypes, and 2) if aerosolized delivery of let-7b to the lungs could minimize potential systemic side effects.